A grandparent's habits die hard

September 22, 2006

A boy whose grandfather had access to abundant food as a teen may be more likely to die young. Robert Winston investigates the before-birth influences that can alter a person's life

At the end of the first chapter of The Life and Opinions of Tristram Shandy , Mrs Shandy asks: "Pray, my dear, have you not forgot to wind up the clock?" To which Tristram's distracted father responds: "Good G-! Did ever woman, since the creation of the world, interrupt a man with such a silly question?"

And once he is born, Tristram is trapped thereafter in a time warp, his whole life (and the book about him) muddled by time. As he says: "I wish either my father or my mother, or indeed both of them, as they were in duty both equally bound to it, had minded what they were about when they begot me; had they duly considered how much depended upon what they were then doing."

Lawrence Sterne was writing in 1759, but this idea - that events at the time of conception, or during gestation, influence not only the outcome of a pregnancy but also the developing child - has prevailed since earliest written records. There is evidence for this in cuneiform tablets from Sumer and in papyri from ancient Egypt. The biblical account in Genesis , when Jacob encourages the birth of speckled sheep (probably a genetically recessive characteristic) in Laban's flock of pure whites, by showing them black-and-white whittled sticks at the moment of conception, suggests that this notion has been widely prevalent for a very long time indeed.

The discoveries of monk Gregor Mendel, who died in 1884, led to a more "rational" understanding of inheritance. But the implications of his work were not fully accepted until more than 40 years after his original observations. His detailed experiments with about 28,000 pea plants gave birth to the idea of the gene being the unit of inheritance, with the Laws of Inheritance named after him. That insight, and the rising importance of the theory of evolution promulgated by Charles Darwin, who died two years before Mendel (and who may just have known of his work), led to a radical change in our ideas of inherited characteristics.

These ideas were not universally accepted very quickly. It took until the 1920s, when it became widely agreed that the genetic variation in populations occurred because of mutations in genes. Phenotypic changes - those in the constitution or appearance of an organism - were seen to be gradual as a response to the pressures of natural selection, which selected those inherited characteristics that better matched the organism with its environment. Subsequently, the modern science of molecular biology showed how the structure of the DNA with its base-pair sequences influences the phenotype by producing specific changes in the RNA and the manufacture of various proteins. And it also became clearer how the maternal and paternal chromosomes carrying the genes were passed to their offspring.

But this knowledge led to rather determinist notions about human genetics. It was easy to think of a gene consistently producing just one aspect of the phenotype, but this is far from the complete story. Genes can produce their influence in ways that are much more subtle than was widely understood.

In the past 15 years or so, there has been increasing evidence that the environment can have a much greater effect on the way genes work than was realised in Mendel's original concept. There is evidence, too, that the environment that prevails during an individual's early development can radically affect later life. These early influences may be particularly important when the individual is in utero. There is strong evidence that many of these effects may be caused by chemical changes in genes and may immediately alter the characteristics of succeeding generations.

One compelling recent discovery was that disease in middle or old age could have its origins in events before birth. David Barker, from Southampton University, trawled through a huge number of records of the births of children in Hertfordshire just before, during and after the First World War. Most of the mothers had normal pregnancies. But inevitably there were some hospital records of women with complicated pregnancies. Some of their babies experienced a deficient environment while in utero and were not well nourished, being born well below normal birthweight in consequence.

In general, the babies who were born much smaller than average turned out to be at increased risk of ill health in later life. A far greater proportion of the adults who started life as very small babies died from coronary heart disease before the age of 65 years. The beginning of their life had been spent in a suboptimal milieu, and the effort of attempting to compensate for this left them with constitutional scars that had grave effects decades later. These babies were, in effect, mismatched to their early environment and had tried to adapt to survive. Barker and his colleagues subsequently showed that heart disease was not the only risk. They were also more likely to suffer the related diseases of stroke, high blood pressure and diabetes by the time they reached middle age.

More remarkable are observations that the environment during early development can produce striking effects in later generations. In 2001, Lars Bygren and his colleagues in Sweden published studies showing how some boys born in 1905 seemed adversely affected by their grandparents' diet. In particular, their grandfathers' access to food affected the longevity of these boys. In an isolated part of northern Sweden there had been regular crop failures and bumper harvests in different years between 1799 and 1880, and these had been very well documented. If the paternal grandfather had had access to copious food from a bumper crop during the time when he went through puberty, his grandchild - if male - was more likely to die at a younger than average age. No cause and effect has been firmly established.

Yet the higher incidence of diabetes in these grandsons suggests that a plentiful diet produced chemical changes in the genes on the Y chromosome of their grandparents' germ cells during a critical stage of early development. These changes could have affected how the genes in their sperm expressed when they produced their children. So the environment of the grandparent had a deleterious effect on the boys (who carried that Y chromosome) two generations later.

The latest in the nature/nurture debate comes from researchers Peter Gluckman and Mark Hanson. In Mismatch: Why our World no Longer Fits our Bodies they place the intriguing influences that arise during development within the context of how humans evolved, because we now live in a very different world from that our species first inhabited. It is becoming increasingly clear that how individuals are matched or mismatched with their early environment and how they adapt can have profound effects on their health. Although we smile at Tristram Shandy's curious predicament, perhaps the ancient intuitive understanding of what influences developing humans was not so wide of the mark.

Lord Winston is professor of fertility studies at Imperial College School of Medicine, London. This is an edited version of the foreword taken from Mismatch , Oxford University Press, £16.99.

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